The IGF-1 receptor signaling system plays an important role in tumor proliferation and survival and is implicated in inhibition of tumor apoptosis. In addition and independent of its mitogenic properties, IGF-1R activation can protect against or at least retard programmed cell death in vitro and in vivo (Harrington et al., EMBO J. 13 (1994) 3286-3295; Sell et al., Cancer Res. 55 (1995) 303-305; Singleton et al., Cancer Res. 56 (1996) 4522-4529). A decrease in the level of IGF-1R below wild type levels was also shown to cause massive apoptosis of tumor cells in vivo (Resnicoff et al., Cancer Res. 55 (1995) 2463-2469; Resnicoff et al., Cancer Res. 55 (1995) 3739-3741). Overexpression of either ligand (IGF) and/or the receptor is a feature of various tumor cell lines and can lead to tumor formation in animal models. Overexpression of human IGF-1R resulted in ligand-dependent anchorage-independent growth of NIH 3T3 or Rat-1 fibroblasts and inoculation of these cells caused a rapid tumor formation in nude mice (Kaleko et al., Mol. Cell. Biol. 10 (1990) 464-473; Prager et al., Proc. Natl. Acad. Sci. USA 91 (1994) 2181-2185). Transgenic mice overexpressing IGF-II specifically in the mammary gland develop mammary adenocarcinoma (Bates et al., Br. J. Cancer 72 (1995) 1189-1193) and transgenic mice overexpressing IGF-II under the control of a more general promoter develop an elevated number and wide spectrum of tumor types (Rogler et al., J. Biol. Chem. 269 (1994) 13779-13784). One example among many for human tumors overexpressing IGF-I or IGF-II at very high frequency (>80%) are Small Cell Lung Carcinomas (Quinn et al., J. Biol. Chem. 271 (1996) 11477-11483). Signaling by the IGF system seems to be also required for the transforming activity of certain oncogenes. Fetal fibroblasts with a disruption of the IGF-1R gene cannot be transformed by the SV40 T antigen, activated Ha-ras, or a combination of both (Sell et al., Proc. Natl. Acad. Sci. USA 90 (1993) 11217-11221; Sell et al., Mol. Cell. Biol. 14 (1994) 3604-3612), and the E5 protein of the bovine papilloma virus is also no longer transforming (Morrione et al., J. Virol. 69 (1995) 5300-5303). Interference with the IGF/IGF-1R system was also shown to reverse the transformed phenotype and to inhibit tumor growth (Trojan et al., Science 259 (1993) 94-97; Kalebic et al., Cancer Res. 54 (1994) 5531-5534; Prager et al., Proc. Natl. Acad, Sci. USA 91 (1994) 2181-2185; Resnicoff et al., Cancer Res. 54 (1994) 2218-2222; Resnicoff et al., Cancer Res. 54 (1994) 4848-4850; Resnicoff et al., Cancer Res. 55 (1995) 2463-2469. For example, mice injected with rat prostate adenocarcinoma cells (PA-III) transfected with IGF-1R antisense cDNA (729 bp) develop tumors 90% smaller than controls or remained tumor-free after 60 days of observation (Burfeind et al., Proc. Natl. Acad. Sci. USA 93 (1996) 7263-7268). IGF-1R mediated protection against apoptosis is independent of de-novo gene expression and protein synthesis. Thus, IGF-1 likely exerts its anti-apoptotic function via the activation of preformed cytosolic mediators.
Some signaling substrates which bind to the IGF-1R (e.g. IRS-1, SHC, p85 PI3 kinase etc., for details see below) have been described. However, none of these transducers is unique to the IGF-1R and thus could be exclusively responsible for the unique biological features of the IGF-1R compared to other receptor tyrosine kinase including the insulin receptor. This indicates that specific targets of the IGF-1R (or at least the IGF-receptor subfamily) might exist which trigger survival and counteract apoptosis and thus are prime pharmaceutical targets for anti-cancer therapy.
By using the yeast two-hybrid system it was shown that p85, the regulatory domain of phosphatidyl inositol 3 kinase (PI3K), interacts with the IGF-1R (Lamothe, B., et al., FEBS Lett. 373 (1995) 51-55; Tartare-Decker, S., et al., Endocrinology 137 (1996) 1019-1024). However binding of p85 to many other receptor tyrosine kinases of virtually all families is also seen. Another binding partner of the IGF-1R defined by two-hybrid screening is SHC which binds also to other tyrosine kinases such as trk, met, EGF-R and the insulin receptor (Tartare-Deckert, S., et al., J. Biol. Chem. 270 (1995) 23456-23460). The insulin receptor substrate 1 (IRS-1) and insulin receptor substrate 2 (IRS-2) were also found to both interact with the IGF-1R as well as the insulin receptor (Tartare-Deckert, S., et al., J. Biol. Chem. 270 (1995) 23456-23460; He, W., et al., J. Biol. Chem. 271 (1996) 11641-11645; Dey, R. B., et al., Mol. Endocrinol. 10 (1996) 631-641). Grb 10 which interacts with the IGF-1R also shares many tyrosine kinases as binding partners, e.g. met, insulin receptor, kit and abl (Dey, R. B., et al., Mol. Endocrinol. 10 (1996) 631-641; Morrione, A., et al., Cancer Res. 56 (1996) 3165-3167). The phosphatase PTP1D (syp) shows also a very promiscuous binding capacity, i.e. binds to IGF-1R, insulin receptor, met and others (Rocchi, S., et al., Endocrinology 137 (1996) 4944-4952). More recently, mSH2-B and vav were described as binders of the IGF-1R, but interaction is also seen with other tyrosine kinases, e.g. mSH2-B also bind to ret and the insulin receptor (Wang, J., and Riedel, H., J. Biol. Chem. 273 (1998) 3136-3139). Taken together, the so far described IGF-1R binding proteins represent relatively unspecific targets for therapeutic approaches, or are in the case of the insulin receptor substrates (IRS-1, IRS-2) indispensable for insulin-driven activities.